Fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether (also named as sevoflurane) is a widely applied inhalation anesthetics, which shows advantages of low blood & air partition coefficient, nonirritant, free of inflammability and explosion, stable and quick anesthesia induction, easy operation, revivification within short period, manageable controlled anesthetic depth, etc., thus presenting wide application in operation anesthesia.
There are 6 major preparation methods of fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether, ie. with reaction of CX2F2 (X is halogen) with 1,1,1,3,3,3-hexafluoroisopropanol, 1,1,1,3,3,3-hexafluoroisopropanol with formaldehyde (trioxymethylene) and non-aqueous hydrogen fluoride in the presence of concentrated sulfuric acid as dehydrant, 1,1,1,3,3,3-hexafluoroisopropanol with CH2FOCH2F, (CF3)2CHOCH2CL with fluorinating reagents, and bromine trifluoride with (CN)2CHOCH3, etc.
U.S. Pat. No. 6,303,831 discloses a method of preparing halomethyl hexafluoroisopropyl ether by reacting 1,1,1,3,3,3-hexafluoroisopropanol with CX2F2 (X is halogen) in the presence of alkality, followed by sevoflurane in the presence of fluorinating reagents following fluorination. Reaction for 18 h will help convert 1,1,1,3,3,3-hexafluoroisopropanol up to 92% and yield sevoflurane up to 40%. The major disadvantages of such preparation method are long reaction time, reaction in two steps, low rate of feedstock conversion (less selection of product), low yield, high price of feedstock CBr2F2 and Cl2F2, etc.
U.S. Pat. No. 3,683,092, U.S. Pat. No. 3,689,571 and U.S. Pat. No. 3,911,024 disclose a method of preparing sevoflurane by reacting chloromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether with potassium fluoride, sodium fluoride, hydrogen fluoride or bromine trifluoride following halogen exchange. In the presence of potassium fluoride and sodium fluoride acting as fluorinating reagents, high-boiling point solvent, like sulfolane, is required to aid reaction at high temperature up to 250-325° C. and high pressure up to 60-80 atmos. Such reaction may last a long period with low yield. In the presence of non-aqueous hydrogen fluoride acting as fluorinating reagent, reaction may occur at temperature of 50-80° C. and at atmospheric pressure, giving low rate of conversion for feedstock and 50-60% of yield. In the presence of bromine trifluoride acting as fluorinating reagent, reaction may easily take place. However, bromine trifluoride is pretty expensive. The above 3 patents also disclose a method of producing methyl-2,2,2-trifluoro-(trifluoromethane) ethyl ether first by reacting 1,1,1,3,3,3-hexafluoroisopropanol with dimethyl sulfate and sodium hydroxide solution, and then chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether by chloridizing methyl-2,2,2-trifluoro-(trifluoromethane) ethyl ether with chlorine. It is a complex reaction.
WO97/25303 and US2004/00730070 provide a method of preparing methyl chloride 1,1,1,3,3,3-hexafluoroisopropyl ether, plus unreacted twin (methyl chloride) ether and acetal, by mixing twin (methyl chloride) ether (CH2FOCH2F), 1,1,1,3,3,3-hexafluoroisopropanol with sulfuric acid. The reaction requires CH2FOCH2F as feedstock not easily available and gives low yield as low as 30% (measured as 1,1,1,3,3,3-hexafluoroisopropanol).
U.S. Pat. No. 4,250,334, U.S. Pat. No. 4,469,898 and U.S. Pat. No. 6,469,219 provide a method of producing sevoflurane with fluoromethylation process, ie. add concentrated sulfuric acid and hydrogen fluoride into paraformal-dehyde to obtain a reaction mixture, and then pipette 1,1,1,3,3,3-hexafluoroisopropanol into the mixture under the heating condition to obtain the gas to be collected. The method, however, may generate dimenthoxym ethane, acetal and other byproducts, plus unavoidable fluoro-ether products other than methyl fluoride-1,1,1,3,3,3-hexafluoroisopropyl ether, with 1,1,1,3,3,3-hexafluoroisopropanol conversion rate of only 33-38%. Meanwhile, the target product—fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether partially forms fluoromethyl 1,1,3,3,3-pentafluoroisopropenyl ether following decomposition reaction. Such two products are not easily separated due to close boiling point. Furthermore, the process requires a large amount of concentrated sulfuric acid as dehydrant and hydrogen chloride as fluorating agent. Hydrogen chloride is so corrosive that equipment and pipelines impose high requirement on its material. Reaction will give rise to a large amount of inorganic or organic acid waste water, thus bringing about many serious problems on treatment of three wastes (waste gas; waste water; industrial residue) for the commercial production.
U.S. Pat. No. 3,897,502 provides a method of producing fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether by subjecting methyl-2,2,2-trifluoro-1-(trifluoromethane) ethyl ether to 20% fluoride diluted with argon with fluoridation. The method gives low yield, and used fluoride is highly toxic and expensive, which is not easily controlled in applications.
Therefore, it is necessary to develop a new preparation method of fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether to address the above concerns.